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    Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy

    • Autor
      Garcia Diaz, Beatriz; Garone, Caterina; Barca, Emanuele; Mojahed, Hamed; Gutiérrez, Purificación; Pizzorno, Giuseppe; Tanji, Kurenai; Arias Mendoza, Fernando; Quinzii, Catarina M; Hirano, Michio
    • Fecha
      2014
    • Editorial/Editor
      Oxford University Press
    • Palabras clave
      Mitocondrias
    • Resumen
      Balanced pools of deoxyribonucleoside triphosphate precursors are required for DNA replication, and alterations of this balance are relevant to human mitochondrial diseases including mitochondrial neurogastrointestinal encephalopathy. In this disease, autosomal recessive TYMP mutations cause severe reductions of thymidine phosphorylase activity; marked elevations of the pyrimidine nucleosides thymidine and deoxyuridine in plasma and tissues, and somatic multiple deletions, depletion and site-specific point mutations of mitochondrial DNA. Thymidine phosphorylase and uridine phosphorylase double knockout mice recapitulated several features of these patients including thymidine phosphorylase activity deficiency, elevated thymidine and deoxyuridine in tissues, mitochondrial DNA depletion, respiratory chain defects and white matter changes. However, in contrast to patients with this disease, mutant mice showed mitochondrial alterations only in the brain. To test the hypothesis that elevated levels of nucleotides cause unbalanced deoxyribonucleoside triphosphate pools and, in turn, pathogenic mitochondrial DNA instability, we have stressed double knockout mice with exogenous thymidine and deoxyuridine, and assessed clinical, neuroradiological, histological, molecular, and biochemical consequences. Mutant mice treated with exogenous thymidine and deoxyuridine showed reduced survival, body weight, and muscle strength, relative to untreated animals. Moreover, in treated mutants, leukoencephalopathy, a hallmark of the disease, was enhanced and the small intestine showed a reduction of smooth muscle cells and increased fibrosis.
    • URI
      https://hdl.handle.net/10630/32327
    • DOI
      https://dx.doi.org/10.1093/brain/awu068
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    manuscript submitted1 Brain.pdf (2.044Mb)
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    REPOSITORIO INSTITUCIONAL UNIVERSIDAD DE MÁLAGA
    REPOSITORIO INSTITUCIONAL UNIVERSIDAD DE MÁLAGA
     

     

    REPOSITORIO INSTITUCIONAL UNIVERSIDAD DE MÁLAGA
    REPOSITORIO INSTITUCIONAL UNIVERSIDAD DE MÁLAGA